Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts

Objective: Immunosuppressive agents have been proposed to reduce neointimal hyperplasia in synthetic vascular grafts. Thus, the purpose of the present study was to evaluate the safety and efficacy of rapamycins (systemic vs. local vs. oral administration) and mycophenolate mofetil (MMF) to reduce intimal hyperplasia in infrarenal synthetic vascular grafts of the rat. Methods: Fifty-four Wistar rats (250 g) completed the study after a synthetic vascular graft (ePTFE, Gore-tex, 2 mm diameter, 10 mm length) was implanted end-to-end in the infrarenal aorta. The animals were divided into three groups: group 1 consisted of 12 control animals, group 2 consisted of 37 rats receiving rapamycins, either per os (RAD, 1.5 or 3 mg/kg), intraperitoneally (RPM, 1.5 or 3 mg/kg) or locally (RPM soaking of the graft); and in group 3 (n = 5), MMF (40 mg/kg) was administered orally. The animals were followed weekly with weight controls and signs of toxicity for 30 (n = 37) and 60 (n = 17) days, respectively. All animals were sacrificed and underwent histological examination at completion of the study. Results: All animals survived in groups 1 and 3, but five died in group 2. The weight gain was normal in all groups, except for the subgroup 2a receiving high dose rapamycins orally. All rats in group 3 suffered from diarrhea, whereas animals receiving high dose rapamycins showed toxic signs (hair loss, wound healing problems). Histological examination showed a significant increase in intimal hyperplasia in group 1 (0.03±0.01 and 0.14±0.05 μm after 30 and 60 days, respectively; P < 0.01). Rapamycins in either application or dosage had no significant effect on intimal hyperplasia. Conclusions: Local or systemic administration of rapamycins has no effect on intimal hyperplasia in synthetic vascular grafts. In contrast, toxic signs with weight loss were observed in animals treated with high dose rapamycins, but not in those treated with MMF. Thus, in the rat model, immunosuppresssion with rapamycins or MMF cannot be recommended for the prevention of intimal hyperplasia in the synthetic vascular graft mode

\u3cem\u3eABCC9\u3c/em\u3e Gene Polymorphism Is Associated with Hippocampal Sclerosis of Aging Pathology

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer\u27s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer\u27s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer\u27s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor

Type II Heat-Labile Enterotoxins from 50 Diverse Escherichia coli Isolates Belong Almost Exclusively to the LT-IIc Family and May Be Prophage Encoded

Some enterotoxigenic Escherichia coli (ETEC) produce a type II heat-labile enterotoxin (LT-II) that activates adenylate cyclase in susceptible cells but is not neutralized by antisera against cholera toxin or type I heat-labile enterotoxin (LT-I). LT-I variants encoded by plasmids in ETEC from humans and pigs have amino acid sequences that are ≥95% identical. In contrast, LT-II toxins are chromosomally encoded and are much more diverse. Early studies characterized LT-IIa and LT-IIb variants, but a novel LT-IIc was reported recently. Here we characterized the LT-II encoding loci from 48 additional ETEC isolates. Two encoded LT-IIa, none encoded LT-IIb, and 46 encoded highly related variants of LT-IIc. Phylogenetic analysis indicated that the predicted LT-IIc toxins encoded by these loci could be assigned to 6 subgroups. The loci corresponding to individual toxins within each subgroup had DNA sequences that were more than 99% identical. The LT-IIc subgroups appear to have arisen by multiple recombinational events between progenitor loci encoding LT-IIc1- and LT-IIc3-like variants. All loci from representative isolates encoding the LT-IIa, LT-IIb, and each subgroup of LT-IIc enterotoxins are preceded by highly-related genes that are between 80 and 93% identical to predicted phage lysozyme genes. DNA sequences immediately following the B genes differ considerably between toxin subgroups, but all are most closely related to genomic sequences found in predicted prophages. Together these data suggest that the LT-II loci are inserted into lambdoid type prophages that may or may not be infectious. These findings raise the possibility that production of LT-II enterotoxins by ETEC may be determined by phage conversion and may be activated by induction of prophage, in a manner similar to control of production of Shiga-like toxins by converting phages in isolates of enterohemmorhagic E. coli

A Solution to the Strong CP Problem with Gauge-Mediated Supersymmetry Breaking

We demonstrate that a certain class of low scale supersymmetric ``Nelson-Barr'' type models can solve the strong and supersymmetric CP problems while at the same time generating sufficient weak CP violation in the $K^{0}-\bar{K}^{0}$ system. In order to prevent one-loop corrections to $\bar{\theta}$ which violate bounds coming from the neutron electric dipole moment (EDM), one needs a scheme for the soft supersymmetry breaking parameters which can naturally give sufficient squark degeneracies and proportionality of trilinear soft supersymmetry-breaking parameters to Yukawa couplings. We show that a gauge-mediated supersymmetry breaking sector can provide the needed degeneracy and proportionality, though that proves to be a problem for generic Nelson-Barr models. The workable model we consider here has the Nelson-Barr mass texture enforced by a gauge symmetry; one also expects a new U(1) gauge superfield with mass in the TeV range. The resulting model is predictive. We predict a measureable neutron EDM and the existence of extra vector-like quark superfields which can be discovered at the LHC. Because the $3\times 3$ Cabbibo-Kobayashi-Maskawa matrix is approximately real, the model also predicts a flat unitarity triangle and the absence of substantial CP violation in the $B$ system at future $B$ factories. We discuss the general issues pertaining to the construction of such a workable model and how they lead to the successful strategy. A detailed renormalization group study is then used to establish the feasibility of the model considered.Comment: Proof-read version to appear in Phys. Rev.

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Grand Challenges for Biological and Environmental Research: A Long-Term Vision

The interactions and feedbacks among plants, animals, microbes, humans, and the environment ultimately form the world in which we live. This world is now facing challenges from a growing and increasingly affluent human population whose numbers and lifestyles are driving ever greater energy demand and impacting climate. These and other contributing factors will make energy and climate sustainability extremely difficult to achieve over the 20-year time horizon that is the focus of this report. Despite these severe challenges, there is optimism that deeper understanding of our environment will enable us to mitigate detrimental effects, while also harnessing biological and climate systems to ensure a sustainable energy future. This effort is advanced by scientific inquiries in the fields of atmospheric chemistry and physics, biology, ecology, and subsurface science - all made possible by computing. The Office of Biological and Environmental Research (BER) within the Department of Energy's (DOE) Office of Science has a long history of bringing together researchers from different disciplines to address critical national needs in determining the biological and environmental impacts of energy production and use, characterizing the interplay of climate and energy, and collaborating with other agencies and DOE programs to improve the world's most powerful climate models. BER science focuses on three distinct areas: (1) What are the roles of Earth system components (atmosphere, land, oceans, sea ice, and the biosphere) in determining climate? (2) How is the information stored in a genome translated into microbial, plant, and ecosystem processes that influence biofuel production, climate feedbacks, and the natural cycling of carbon? (3) What are the biological, geochemical, and physical forces that govern the behavior of Earth's subsurface environment? Ultimately, the goal of BER science is to support experimentation and modeling that can reliably predict the outcomes and behaviors of complex biological and environmental systems, leading to robust solutions for DOE missions and strategic goals. In March 2010, the Biological and Environmental Research Advisory Committee held the Grand Challenges for Biological and Environmental Research: A Long-Term Vision workshop to identify scientific opportunities and grand challenges for BER science in the coming decades and to develop an overall strategy for drafting a long-term vision for BER. Key workshop goals included: (1) Identifying the greatest scientific challenges in biology, climate, and the environment that DOE will face over a 20-year time horizon. (2) Describing how BER should be positioned to address those challenges. (3) Determining the new and innovative tools needed to advance BER science. (4) Suggesting how the workforce of the future should be trained in integrative system science. This report lays out grand research challenges for BER - in biological systems, climate, energy sustainability, computing, and education and workforce training - that can put society on a path to achieve the scientific evidence and predictive understanding needed to inform decision making and planning to address future energy needs, climate change, water availability, and land use

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens